Ibrutinib prodrugs, pharmaceutical compositions thereof, and methods of use

ABSTRACT

Prodrugs of ibrutinib, pharmaceutical compositions comprising the prodrugs, and methods of using the prodrugs and pharmaceutical compositions for treating autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions are disclosed.

FIELD

Disclosed herein are ibrutinib prodrugs, pharmaceutical compositionscomprising ibrutinib prodrugs, and methods of using ibrutinib prodrugsand pharmaceutical compositions thereof for treating autoimmune diseasesor conditions, heteroimmune diseases or conditions, cancer, includinglymphoma, and inflammatory diseases or conditions.

BACKGROUND

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is approved inUnited States for the treatment of mantle cell lymphoma, chroniclymphocytic leukemia, and lymphoplasmacytic lymphoma (U.S. Pat. No.7,514,444, U.S. Pat. No. 7,718,662, and U.S. Pat. No. 8,735,403). Therecommended dose of ibrutinib is 420 to 560 mg orally once daily.However, the absolute bioavailability of ibrutinib in fasted humans(n=8) was 2.9% (90% CI=2.1-3.9) and doubled when combined with a meal(European Medicines Agency).

The need for higher ibrutinib dosage to counter its low oralbioavailability may be responsible for adverse side effects such asnausea or emesis, dizziness and diarrhea. Moreover, the low oralbioavailability may result in variable absorption and therapeuticresponse.

SUMMARY

Ibrutinib prodrugs having higher oral bioavailability than the parentcompound may: reduce gastrointestinal side effects/toxicity such asnausea or emesis, dizziness and diarrhea; facilitate the use of lowerdoses; reduce food effects; reduce interpatient treatment variability;and enhance the efficacy/responder rate.

In a first aspect, compounds of Formula (I) are provided:

or a pharmaceutically acceptable solvate, hydrate, or salt thereof,wherein:

A is selected from N and CR¹¹;

each R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independentlyselected from H, halogen, —CF₃, —CN, —NO₂, OH, NH₂, —L¹-(substituted orunsubstituted alkyl), —L¹-(substituted or unsubstituted alkenyl),—L¹-(substituted or unsubstituted heteroaryl), or —L¹-(substituted orunsubstituted aryl), wherein L¹ is a bond, O, S, —S(═O)—, —S(═O)₂—,—NH—, —C(O)—, —CH₂—, —NHC(O)O—, —NHC(O)—, or —C(O)NH—;

R² is selected from H and lower alkyl;

R³ is L²-X-L³-G, wherein,

-   -   L² is selected from a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted cycloalkylene,        substituted or unsubstituted alkenylene, and substituted or        unsubstituted alkynylene;    -   X is selected from a bond, O, —C(═O)—, S, —S(═O)—, —S(═O)₂—,        —NH—, —NR¹⁴—, —NHC(O)—, —C(O)NH—, —NR¹⁴C(O)—, —C(O)NR¹⁴—,        —S(═O)₂NH—, —NHS(═O)₂—, —S(═O)₂NR¹⁴—, —NR¹⁴S(═O)₂—, —OC(O)NH—,        —NHC(O)O—, —OC(O)NR¹⁴—, —NR¹⁴C(O)O—, —CH═NO—, —ON═CH—,        —NR¹⁵C(O)NR¹⁵—, heteroarylene, arylene, —NR¹⁵C(═NR¹⁶)NR¹⁵—,        —NR¹⁵C(═NR¹⁶)—, —C(═NR¹⁶)NR¹⁵—, —OC(═NR¹⁶)—, and —C(═NR¹⁶)O—,        wherein        -   R¹⁴ is selected from H, substituted or unsubstituted lower            alkyl, and substituted or unsubstituted lower cycloalkyl;        -   each R¹⁵ is independently selected from H, substituted or            unsubstituted lower alkyl, and substituted or unsubstituted            lower cycloalkyl; and        -   R¹⁶ is selected from H, —S(═O)₂R¹¹, —S(═O)₂NH₂, —C(O)R¹¹,            —CN, —NO₂, heteroaryl, and heteroalkyl;    -   L³ is selected from a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted cycloalkylene,        substituted or unsubstituted alkenylene, substituted or        unsubstituted alkynylene, substituted or unsubstituted arylene,        substituted or unsubstituted heteroarylene, and substituted or        unsubstituted heterocyclene;    -   or L², X and L³ taken together form a nitrogen containing        heterocyclic ring; and    -   G is selected from the following structures:

Z is selected from the following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower heteroalkyl, substituted or unsubstituted lower cycloalkyl,substituted or unsubstituted lower heterocycloalkyl, and substituted orunsubstituted lower aryl.

In a second aspect, pharmaceutical compositions are provided comprisinga compound of Formula (I) and at least one pharmaceutically acceptablevehicle.

In a third aspect, methods of treating a disease in a patient areprovided comprising administering to a patient in need of such treatmenta pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula (I). In certain embodiments, the diseaseis chosen from an autoimmune diseases or conditions, heteroimmunediseases or conditions, cancer, including lymphoma, and inflammatorydiseases or conditions.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereare a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4TH ED.” Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques can be used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. Standardtechniques can be used for recombinant DNA, oligonucleotide synthesis,and tissue culture and transformation (e.g., electroporation,lipofection). Reactions and purification techniques can be performede.g., using kits of manufacturer's specifications or as commonlyaccomplished in the art or as described herein. The foregoing techniquesand procedures can be generally performed of conventional methods wellknown in the art and as described in various general and more specificreferences that are cited and discussed throughout the presentspecification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods and compositions described herein,which will be limited only by the appended claims.

All publications and patents mentioned herein are incorporated herein byreference in their entirety for the purpose of describing anddisclosing, for example, the constructs and methodologies that aredescribed in the publications, which might be used in connection withthe methods, compositions and compounds described herein. Thepublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the inventors described herein arenot entitled to antedate such disclosure by virtue of prior invention orfor any other reason.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety may also be an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group that hasat least one carbon-carbon double bond, and an “alkyne” moiety refers toa group that has at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, may be branched, straightchain, or cyclic. Depending on the structure, an alkyl group can be amonoradical or a diradical (i.e., an alkylene group). The alkyl groupcould also be a “lower alkyl” having 1 to 6 carbon atoms.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to andincluding 10 carbon atoms, although the present definition also coversthe occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₄ alkyl” or similar designations. By way of exampleonly, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from among methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Thus C₁-C₄ alkyl includes C₁-C₂ alkyl and C₁-C₃ alkyl. Alkyl groups canbe substituted or unsubstituted. Typical alkyl groups include, but arein no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term “non-cyclic alkyl” refers to an alkyl that isnot cyclic (i.e., a straight or branched chain containing at least onecarbon atom). Non-cyclic alkyls can be fully saturated or can containnon-cyclic alkenes and/or alkynes. Non-cyclic alkyls can be optionallysubstituted.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═C(R)—R, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. The alkenyl moiety may bebranched, straight chain, or cyclic (in which case, it would also beknown as a “cycloalkenyl” group). Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).Alkenyl groups can be optionally substituted. Non-limiting examples ofan alkenyl group include —CH═CH₂, —C(CH3)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃.Alkenylene groups include, but are not limited to, —CH═CH—, —C(CH₃)═CH—,—CH═CHCH₂—, —CH═CHCH₂CH₂— and —C(CH₃)═CHCH₂—. Alkenyl groups could have2 to 10 carbons. The alkenyl group could also be a “lower alkenyl”having 2 to 6 carbon atoms.

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C═C—R, wherein R refers to the remainingportions of the alkynyl group, which may be the same or different. The“R” portion of the alkynyl moiety may be branched, straight chain, orcyclic. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group). Alkynyl groupscan be optionally substituted. Non-limiting examples of an alkynyl groupinclude, but are not limited to, —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃, —C≡C—, and—C≡CCH₂—. Alkynyl groups can have 2 to 10 carbons. The alkynyl groupcould also be a “lower alkynyl” having 2 to 6 carbon atoms.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith an alkoxy group, as defined herein.

An “alkenyloxy” group refers to a (alkenyl)O— group, where alkenyl is asdefined herein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkylgroups, taken together with the N atom to which they are attached, canoptionally form a cyclic ring system.

“Alkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine, as defined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). An amide moiety may form a linkage between an amino acidor a peptide molecule and a compound described herein, thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters are known to those of skill in the art and can readily befound in reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

The term “carbocyclic” or “carbocycle” refers to a ring wherein each ofthe atoms forming the ring is a carbon atom. Carbocycle includes aryland cycloalkyl. The term thus distinguishes carbocycle from heterocycle(“heterocyclic”) in which the ring backbone contains at least one atomwhich is different from carbon (i.e a heteroatom). Heterocycle includesheteroaryl and heterocycloalkyl. Carbocycles and heterocycles can beoptionally substituted.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both carbocyclic aryl (e.g., phenyl) andheterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,fluorenyl, and indenyl. Depending on the structure, an aryl group can bea monoradical or a diradical (i.e., an arylene group).

An “aryloxy” group refers to an (aryl)O— group, where aryl is as definedherein.

“Aralkyl” means an alkyl radical, as defined herein, substituted with anaryl group. Non-limiting aralkyl groups include, benzyl, phenethyl, andthe like.

“Aralkenyl” means an alkenyl radical, as defined herein, substitutedwith an aryl group, as defined herein.

The term “cycloalkyl” refers to a monocyclic or polycyclic radical thatcontains only carbon and hydrogen, and may be saturated, partiallyunsaturated, or fully unsaturated. Cycloalkyl groups include groupshaving from 3 to 10 ring atoms. Illustrative examples of cycloalkylgroups include the following moieties:

and the like. Depending on the structure, a cycloalkyl group can be amonoradical or a diradical (e.g., an cycloalkylene group). Thecycloalkyl group could also be a “lower cycloalkyl” having 3 to 8 carbonatoms.

“Cycloalkylalkyl” means an alkyl radical, as defined herein, substitutedwith a cycloalkyl group. Non-limiting cycloalkylalkyl groups includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Herein, whenever the number of carbonatoms in a heterocycle is indicated (e.g., C₁-C₆ heterocycle), at leastone other atom (the heteroatom) must be present in the ring.Designations such as “C₁-C₆ heterocycle” refer only to the number ofcarbon atoms in the ring and do not refer to the total number of atomsin the ring. It is understood that the heterocylic ring can haveadditional heteroatoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Inheterocycles that have two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Binding to a heterocycle can be at aheteroatom or via a carbon atom. Non-aromatic heterocyclic groupsinclude groups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a4-membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5-membered heterocyclic group is thiazolyl. An example of a6-membered heterocyclic group is pyridyl, and an example of a10-membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydropyranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one. Depending on thestructure, a heterocycle group can be a monoradical or a diradical(i.e., a heterocyclene group).

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Illustrative examplesof heteroaryl groups include the following moieties:

and the like. Depending on the structure, a heteroaryl group can be amonoradical or a diradical (i.e., a heteroarylene group).

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Heterocycloalkyl ringscan be formed by three, four, five, six, seven, eight, nine, or morethan nine atoms. Heterocycloalkyl rings can be optionally substituted.In certain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples of heterocycloalkyls include, but arenot limited to, lactams, lactones, cyclic imides, cyclic thioimides,cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloalkylene group).

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo and iodo.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures in which at leastone hydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In other embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another.

The term “fluoroalkyl,” as used herein, refers to alkyl group in whichat least one hydrogen is replaced with a fluorine atom. Examples offluoroalkyl groups include, but are not limited to, —CF₃, —CH₂CF₃,—CF₂CF₃, —CH₂CH₂CF₃ and the like.

As used herein, the terms “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl andalkynyl radicals in which one or more skeletal chain atoms is aheteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus orcombinations thereof. The heteroatom(s) may be placed at any interiorposition of the heteroalkyl group or at the position at which theheteroalkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₃, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may beconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “sulfonyl” group refers to a —S(═O)—R.

A “sulfonyl” group refers to a —S(═O)₂—R.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

A “alkylthioalkyl” group refers to an alkyl group substituted with a—S-alkyl group.

As used herein, the term “O-carboxy” or “acyloxy” refers to a group offormula RC(═O)O—.

“Carboxy” means a —C(O)OH radical.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

“Acyl” refers to the group —C(O)R.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

As used herein, the term “cyano” refers to a group of formula —CN.

“Cyanoalkyl” means an alkyl radical, as defined herein, substituted withat least one cyano group.

As used herein, the term “N-sulfonamido” or “sulfonylamino” refers to agroup of formula RS(═O)₂NH—.

As used herein, the term “O-carbamyl” refers to a group of formula—OC(═O)NR².

As used herein, the term “N-carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O-thiocarbamyl” refers to a group of formulaOC(═S)NR².

As used herein, the term “N-thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C-amido” refers to a group of formula—C(═O)NR².

“Aminocarbonyl” refers to a —CONH₂ radical.

As used herein, the term “N-amido” refers to a group of formulaRC(═O)NH—.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono-and di-substituted amino groups, and the protected derivatives thereof.By way of example an optional substituents may be LsRs, wherein each Lsis independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—,—NHC(O)O—, -(substituted or unsubstituted C₁-C₆ alkyl), or -(substitutedor unsubstituted C₂-C₆ alkenyl); and each Rs is independently selectedfrom H, (substituted or unsubstituted C₁-C₄ alkyl), (substituted orunsubstituted C₃-C₆ cycloalkyl), heteroaryl, or heteroalkyl. Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above.

The term “Michael acceptor moiety” refers to a functional group that canparticipate in a Michael reaction, wherein a new covalent bond is formedbetween a portion of the Michael acceptor moiety and the donor moiety.The Michael acceptor moiety is an electrophile and the “donor moiety” isa nucleophile. The “G” groups presented in Formula (I) are non-limitingexamples of Michael acceptor moieties.

The term “nucleophile” or “nucleophilic” refers to an electron richcompound, or moiety thereof. An example of a nucleophile includes, butin no way is limited to, a cysteine residue of a molecule, such as, forexample Cys 481 of Btk.

The term “electrophile”, or “electrophilic” refers to an electron pooror electron deficient molecule, or moiety thereof. Examples ofelectrophiles include, but in no way are limited to, Michael acceptormoieties.

The term “acceptable” or “pharmaceutically acceptable”, with respect toa formulation, composition or ingredient, as used herein, means havingno persistent detrimental effect on the general health of the subjectbeing treated or does not abrogate the biological activity or propertiesof the compound, and is relatively nontoxic.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a protein that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the protein, such as, for example, Btk.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a protein that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” refers to a compound, the presenceof which results in a decrease in the magnitude of a biological activityof a protein. In certain embodiments, the presence of an antagonistresults in complete inhibition of a biological activity of a protein,such as, for example, Btk. In certain embodiments, an antagonist is aninhibitor.

As used herein, “amelioration” of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein, such as compounds of Formula (I), dosed that isdelivered into the general circulation of the animal or human beingstudied. The total exposure (AUC(0-∞)) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which compounds disclosedherein, such as compounds of any of Formula (I), are absorbed into thegeneral circulation when the pharmaceutical composition is taken orallyas compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsdisclosed herein, such as compounds of Formula (I), in the plasmacomponent of blood of a subject. It is understood that the plasmaconcentration of compounds of Formula (I) may vary significantly betweensubjects, due to variability with respect to metabolism and/or possibleinteractions with other therapeutic agents. In accordance with oneembodiment disclosed herein, the blood plasma concentration of thecompounds Formula (I), may vary from subject to subject. Likewise,values such as maximum plasma concentration (Cmax) or time to reachmaximum plasma concentration (Tmax), or total area under the plasmaconcentration time curve (AUC(0-∞)) may vary from subject to subject.Due to this variability, the amount necessary to constitute “atherapeutically effective amount” of a compound of Formula (1) may varyfrom subject to subject.

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP-000052).

The term “Bruton's tyrosine kinase homolog,” as used herein, refers toorthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse(GenBank Acession No. AAB47246), dog (GenBank Acession No. XP-549139),rat (GenBank Acession No. NP-001007799), chicken (GenBank Acession No.NP-989564), or zebra fish (GenBank Acession No. XP-698117), and fusionproteins of any of the foregoing that exhibit kinase activity towardsone or more substrates of Bruton's tyrosine kinase (e.g. a peptidesubstrate having the amino acid sequence “AVLESEEELYSSARQ”).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case may be determined using techniques, such as a doseescalation study. The term “therapeutically effective amount” includes,for example, a prophylactically effective amount. An “effective amount”of a compound disclosed herein is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. It is understood that “an effect amount” or “atherapeutically effective amount” can vary from subject to subject, dueto variation in metabolism of the compound of Formula (I), age, weight,general condition of the subject, the condition being treated, theseverity of the condition being treated, and the judgment of theprescribing physician. By way of example only, therapeutically effectiveamounts may be determined by routine experimentation, including but notlimited to a dose escalation clinical trial.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. By way of example, “enhancing”the effect of therapeutic agents refers to the ability to increase orprolong, either in potency or duration, the effect of therapeutic agentson during treatment of a disease, disorder or condition. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of a therapeutic agent in the treatmentof a disease, disorder or condition. When used in a patient, amountseffective for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

The term “homologous cysteine,” as used herein refers to a cysteineresidue found with in a sequence position that is homologous to that ofcysteine 481 of Bruton's tyrosine kinase, as defined herein. Forexample, cysteine 482 is the homologous cysteine of the rat ortholog ofBruton's tyrosine kinase; cysteine 479 is the homologous cysteine of thechicken ortholog; and cysteine 481 is the homologous cysteine in thezebra fish ortholog. In another example, the homologous cysteine of TXK,a Tec kinase family member related to Bruton's tyrosine, is Cys 350.Other examples of kinases having homologous cysteines are shown inFIG. 1. See also the sequence alignments of tyrosine kinases (TK)published on the world wide web atkinase.com/human/kinome/phylogeny.html.

The term “identical,” as used herein, refers to two or more sequences orsubsequences which are the same. In addition, the term “substantiallyidentical,” as used herein, refers to two or more sequences which have apercentage of sequential units which are the same when compared andaligned for maximum correspondence over a comparison window, ordesignated region as measured using comparison algorithms or by manualalignment and visual inspection. By way of example only, two or moresequences may be “substantially identical” if the sequential units areabout 60% identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. Suchpercentages to describe the “percent identity” of two or more sequences.The identity of a sequence can exist over a region that is at leastabout 75-100 sequential units in length, over a region that is about 50sequential units in length, or, where not specified, across the entiresequence. This definition also refers to the complement of a testsequence. By way of example only, two or more polypeptide sequences areidentical when the amino acid residues are the same, while two or morepolypeptide sequences are “substantially identical” if the amino acidresidues are about 60% identical, about 65% identical, about 70%identical, about 75% identical, about 80% identical, about 85%identical, about 90% identical, or about 95% identical over a specifiedregion. The identity can exist over a region that is at least about75-100 amino acids in length, over a region that is about 50 amino acidsin length, or, where not specified, across the entire sequence of apolypeptide sequence. In addition, by way of example only, two or morepolynucleotide sequences are identical when the nucleic acid residuesare the same, while two or more polynucleotide sequences are“substantially identical” if the nucleic acid residues are about 60%identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. The identitycan exist over a region that is at least about 75-100 nucleic acids inlength, over a region that is about 50 nucleic acids in length, or,where not specified, across the entire sequence of a polynucleotidesequence.

The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as usedherein, refer to inhibition of enzymatic phosphotransferase activity.

The term “irreversible inhibitor,” as used herein, refers to a compoundthat, upon contact with a target protein (e.g., a kinase) causes theformation of a new covalent bond with or within the protein, whereby oneor more of the target protein's biological activities (e.g.,phosphotransferase activity) is diminished or abolished notwithstandingthe subsequent presence or absence of the irreversible inhibitor.

The term “irreversible Btk inhibitor,” as used herein, refers to aninhibitor of Btk that can form a covalent bond with an amino acidresidue of Btk. In one embodiment, the irreversible inhibitor of Btk canform a covalent bond with a Cys residue of Btk; in particularembodiments, the irreversible inhibitor can form a covalent bond with aCys 481 residue (or a homolog thereof) of Btk or a cysteine residue inthe homologous corresponding position of another tyrosine kinase.

The term “isolated,” as used herein, refers to separating and removing acomponent of interest from components not of interest. Isolatedsubstances can be in either a dry or semi-dry state, or in solution,including but not limited to an aqueous solution. The isolated componentcan be in a homogeneous state or the isolated component can be a part ofa pharmaceutical composition that comprises additional pharmaceuticallyacceptable carriers and/or excipients. By way of example only, nucleicacids or proteins are “isolated” when such nucleic acids or proteins arefree of at least some of the cellular components with which it isassociated in the natural state, or that the nucleic acid or protein hasbeen concentrated to a level greater than the concentration of its invivo or in vitro production. Also, by way of example, a gene is isolatedwhen separated from open reading frames which flank the gene and encodea protein other than the gene of interest.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient which will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like. It isconsidered well within the skill of the art for one to determine suchprophylactically effective amounts by routine experimentation,including, but not limited to, a dose escalation clinical trial.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetproteins.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target protein, such as, forexample, Btk, with greater affinity than it binds to a non-targetprotein. In certain embodiments, specific binding refers to binding to atarget with an affinity that is at least 10, 50, 100, 250, 500, 1000 ormore times greater than the affinity for a non-target.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity relative to a non-targetactivity. In certain embodiments, specific modulater refers tomodulating a target activity at least 10, 50, 100, 250, 500, 1000 timesmore than a non-target activity.

The term “substantially purified,” as used herein, refers to a componentof interest that may be substantially or essentially free of othercomponents which normally accompany or interact with the component ofinterest prior to purification. By way of example only, a component ofinterest may be “substantially purified” when the preparation of thecomponent of interest contains less than about 30%, less than about 25%,less than about 20%, less than about 15%, less than about 10%, less thanabout 5%, less than about 4%, less than about 3%, less than about 2%, orless than about 1% (by dry weight) of contaminating components. Thus, a“substantially purified” component of interest may have a purity levelof about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, about 99% or greater.

The term “subject” as used herein, refers to an animal which is theobject of treatment, observation or experiment. By way of example only,a subject may be, but is not limited to, a mammal including, but notlimited to, a human.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

As used herein, the term “target protein” refers to a molecule or aportion of a protein capable of being bound by a selective bindingcompound. In certain embodiments, a target protein is Btk.

The terms “treat,” “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition. The terms “treat,”“treating” or “treatment”, include, but are not limited to, prophylacticand/or therapeutic treatments.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of Btk, in an assay that measures suchresponse.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

Compounds

Certain embodiments provide a compound of Formula (I):

or a pharmaceutically acceptable solvate, hydrate, or salt thereof,wherein:

-   -   A is selected from N and CR¹¹;

each R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independentlyselected from H, halogen, —CF₃, —CN, —NO₂, OH, NH₂, —L¹-(substituted orunsubstituted alkyl), —L¹-(substituted or unsubstituted alkenyl),—L¹-(substituted or unsubstituted heteroaryl), or —L¹-(substituted orunsubstituted aryl), wherein L¹ is a bond, O, S, —S(═O)—, —S(═O)₂—,—NH—, —C(O)—, —CH₂—, —NHC(O)O—, —NHC(O)—, or —C(O)NH—;

R² is selected from H and lower alkyl;

R³ is L²-X-L³-G, wherein,

-   -   L² is selected from a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted cycloalkylene,        substituted or unsubstituted alkenylene, and substituted or        unsubstituted alkynylene;    -   X is selected from a bond, O, —C(═O)—, S, —S(═O)—, —S(═O)₂—,        —NH—, —NR¹⁴—, —NHC(O)—, —C(O)NH—, —NR¹⁴C(O)—, —C(O)NR¹⁴—,        —S(═O)₂NH—, —NHS(═O)₂—, —S(═O)₂NR¹⁴—, —NR¹⁴S(═O)₂—, —OC(O)NH—,        —NHC(O)O—, —OC(O)NR¹⁴—, —NR¹⁴C(O)O—, —CH═NO—, —ON═CH—,        —NR¹⁵C(O)NR¹⁵—, heteroarylene, arylene, —NR¹⁵C(═NR¹⁶)NR¹⁵—,        —NR¹⁵C(═NR¹⁶)—, —C(═NR¹⁶)NR¹⁵—, —OC(═NR¹⁶)—, and —C(═NR¹⁶)O—,        wherein        -   R¹⁴ is selected from H, substituted or unsubstituted lower            alkyl, and substituted or unsubstituted lower cycloalkyl;        -   each R¹⁵ is independently selected from H, substituted or            unsubstituted lower alkyl, and substituted or unsubstituted            lower cycloalkyl; and        -   R¹⁶ is selected from H, —S(═O)₂R¹¹, —S(═O)₂NH₂, —C(O)R¹¹,            —CN, —NO₂, heteroaryl, and heteroalkyl;    -   L³ is selected from a bond, substituted or unsubstituted        alkylene, substituted or unsubstituted cycloalkylene,        substituted or unsubstituted alkenylene, substituted or        unsubstituted alkynylene, substituted or unsubstituted arylene,        substituted or unsubstituted heteroarylene, and substituted or        unsubstituted heterocyclene;    -   or L², X and L³ taken together form a nitrogen containing        heterocyclic ring; and    -   G is selected from the following structures:

Z is selected from the following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower heteroalkyl, substituted or unsubstituted lower cycloalkyl,substituted or unsubstituted lower heterocycloalkyl, and substituted orunsubstituted lower aryl.

In certain embodiments of a compound of Formula (I), A is selected fromN and CR¹¹, wherein R¹¹ is selected from H, substituted or unsubstitutedlower alkyl, substituted or unsubstituted lower heteroalkyl, substitutedor unsubstituted lower cycloalkyl, substituted or unsubstituted lowerheterocycloalkyl, and substituted or unsubstituted lower aryl.

In certain embodiments of a compound of Formula (I), A is N.

In certain embodiments of a compound of Formula (I), A is CR¹¹, whereinR¹¹ is selected from H, methyl, ethyl, n-propyl, cyclopentyl,cyclohexyl, phenyl, and benzyl.

In certain embodiments of a compound of Formula (I), A is CR¹¹, whereinR¹¹ is H.

In certain embodiments of a compound of Formula (I), each R¹ isindependently selected from H, halogen, —CF₃, —CN, —NO₂, OH, and NH₂.

In certain embodiments of a compound of Formula (I), each R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected from H,—L¹-(substituted or unsubstituted alkyl), —L¹-(substituted orunsubstituted alkenyl), —L¹-(substituted or unsubstituted heteroaryl),and —L¹-(substituted or unsubstituted aryl), wherein L¹ is selected froma bond, O, S, —S(═O)—, —S(═O)₂—, —NH—, —C(O)—, —CH₂—, —NHC(O)O—,—NHC(O)—, and —C(O)NH—.

In certain embodiments of a compound of Formula (I), each R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected from H,—L¹-(substituted or unsubstituted alkyl), —L¹-(substituted orunsubstituted alkenyl), —L¹-(substituted or unsubstituted heteroaryl),and —L¹-(substituted or unsubstituted aryl), wherein L¹ is selected froma bond, O, and NH.

In certain embodiments of a compound of Formula (I), each R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected from H,—L¹-(substituted or unsubstituted alkyl), —L¹-(substituted orunsubstituted alkenyl), —L¹-(substituted or unsubstituted heteroaryl),and —L¹-(substituted or unsubstituted aryl), wherein L¹ is O.

In certain embodiments of a compound of Formula (I), each R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected from H and—L¹-(substituted or unsubstituted phenyl), wherein L¹ is O.

In certain embodiments of a compound of Formula (I), each R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected from H and—O-phenyl.

In certain embodiments of a compound of Formula (I), each R^(1a),R^(1b), R^(1d), and R^(1e) is H and R^(1c) is —O-phenyl.

In certain embodiments of a compound of Formula (I), R² is selected fromH and lower alkyl.

In certain embodiments of a compound of Formula (I), R² is selected fromH, methyl, ethyl, n-propyl, and isopropyl.

In certain embodiments of a compound of Formula (I), R² is selected fromH and methyl.

In certain embodiments of a compound of Formula (I), R² is H.

In certain embodiments of a compound of Formula (I), R³ is L²-X-L³-G.

In certain embodiments of a compound of Formula (I), L² is selected froma bond, substituted or unsubstituted alkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstituted alkenylene,and substituted or unsubstituted alkynylene.

In certain embodiments of a compound of Formula (I), L² is selected froma bond, methylene, ethylene, propylene, butylene, cyclopentylene, andcyclohexylene.

In certain embodiments of a compound of Formula (I), X is selected froma bond, O, —C(═O)—, S, —S(═O)—, —S(═O)₂—, —NH—, —NR¹⁴—, —NHC(O)—,—C(O)NH—, —NR¹⁴C(O)—, —C(O)NR¹⁴—, —S(═O)₂NH—, —NHS(═O)₂—, —S(═O)₂NR¹⁴—,—NT¹⁴S(═O)₂—, —OC(O)NH—, —NHC(O)O—, —OC(O)NR¹⁴—, —NR¹⁴C(O)O—, —CH═NO—,—ON═CH—, —NR¹⁵C(O)NR¹⁵—, heteroarylene, arylene, —NR¹⁵C(═NR¹⁶)NR¹⁵—,—NR¹⁵C(═NR¹⁶)—, —C(═NR¹⁶)NR¹⁵—, —OC(═NR¹⁶)—, and —C(═NR¹⁶)O—, whereinR¹⁴ is selected from H, substituted or unsubstituted lower alkyl, andsubstituted or unsubstituted lower cycloalkyl; each R¹⁵ is independentlyselected from H, substituted or unsubstituted lower alkyl, andsubstituted or unsubstituted lower cycloalkyl; and R¹⁶ is selected fromH, —S(═O)₂R¹¹, —S(═O)₂NH₂, —C(O)R¹¹, —CN, —NO₂, heteroaryl, andheteroalkyl.

In certain embodiments of a compound of Formula (I), L² is a bond.

In certain embodiments of a compound of Formula (I), X is selected froma bond, O, —C(═O)—, S, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—,—NHC(O)—, —C(O)NH—, —S(═O)₂NH—, —NHS(═O)₂—, —S(═O)₂NH—, —NHS(═O)₂—,—OC(O)NH—, —NHC(O)O—, —OC(O)NH—, —NHC(O)O—, —CH═NO—, —ON═CH—,—NHC(O)NH—, heteroarylene, arylene, —NHC(═NH)NH—, —NHC(═NH)—,—C(═NH)NH—, —OC(═NH)—, and —C(═NH)O—.

In certain embodiments of a compound of Formula (I), X is selected froma bond and —NH.

In certain embodiments of a compound of Formula (I), X is —NH.

In certain embodiments of a compound of Formula (I), X is a bond.

In certain embodiments of a compound of Formula (I), L² is a bond and Xis a bond.

In certain embodiments of a compound of Formula (I), L³ is selected froma bond, substituted or unsubstituted alkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, substituted or unsubstitutedarylene, substituted or unsubstituted heteroarylene, and substituted orunsubstituted heterocyclene.

In certain embodiments of a compound of Formula (I), L³ is selected froma bond, methylene, ethylene, propylene, butylene, cyclopentylene,cyclohexylene, phenylene, piperidylene, and pyrrolidinylene.

In certain embodiments of a compound of Formula (I), L³ is selected froma bond, 1,2-piperidylene, 1,3-piperidylene, and 1,4-piperidylene.

In certain embodiments of a compound of Formula (I), L³ is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), L² is a bond, X isa bond, and L³ is selected from the following structures:

In certain embodiments of a compound of Formula (I), L², X and L³ takentogether form a nitrogen containing heterocyclic ring.

In certain embodiments of a compound of Formula (I), L², X and L³ takentogether form a nitrogen containing heterocyclic ring selected from thefollowing structures:

In certain embodiments of a compound of Formula (I), G is selected fromthe following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower heteroalkyl, substituted or unsubstituted lower cycloalkyl,substituted or unsubstituted lower heterocycloalkyl, and substituted orunsubstituted lower aryl.

In certain embodiments of a compound of Formula (I), G is selected fromthe following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H, methyl,ethyl, n-propyl, isopropyl, 2-(dimethylamino)ethyl,(dimethylamino)methyl, methoxymethyl, cyclohexyl, and phenyl.

In certain embodiments of a compound of Formula (I), G is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), R³ is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), R³ is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), R³ is the followingstructure:

In certain embodiments of a compound of Formula (I), Z is selected fromthe following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower heteroalkyl, substituted or unsubstituted lower cycloalkyl,substituted or unsubstituted lower heterocycloalkyl, and substituted orunsubstituted lower aryl.

In certain embodiments of a compound of Formula (I), Z is selected fromthe following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H, methyl,ethyl, n-porpyl, isopropyl, isobutyl, tent-butyl, pentyl, neopentyl,n-hexyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, phenyl, and benzyl.

In certain embodiments of a compound of Formula (I), Z is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), Z is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), Z is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), Z is selected fromthe following structures:

In certain embodiments of a compound of Formula (I), A is N; eachR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom H and —O-phenyl; R² is H;

R³ is

and Z is

In certain embodiments of a compound of Formula (I), A is N; eachR^(1a), R^(1b), R^(1d), and R^(1e) is H; R^(1c) is —O-phenyl; R² is H;

R³ is

and Z is

In certain embodiments of a compound of Formula (I), A is N; eachR^(1a), R^(1b), R^(1d), and R^(1e) is H; R^(1c) is —O-phenyl; R² is H;

R³ is

and Z is

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-A-1), Formula (I-A-2), Formula(I-A-3), Formula (I-A-4), Formula (I-A-5), Formula (I-A-6), Formula(I-A-7), Formula (I-A-8), Formula (I-A-9), Formula (I-A-10), Formula(I-A-11), Formula (I-A-12), Formula (I-A-13), Formula (I-A-14), Formula(I-A-15), Formula (I-A-16), Formula (I-A-17), Formula (I-A-18), Formula(I-A-19), and Formula (I-A-20):

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-B-1) and Formula (I-B-2):

In certain embodiments of a compound of Formula (I), the compound ischosen from a compound of Formula (I-C-1) and Formula (I-C-2):

Synthesis

Compounds disclosed herein may be obtained via the synthetic methodsillustrated in Schemes I-A and I-B. General synthetic methods useful inthe synthesis of compounds described herein are available in the art.Starting materials useful for preparing compounds and intermediatesthereof and/or practicing methods described herein are commerciallyavailable or can be prepared by well-known synthetic methods. Themethods presented in the schemes provided by the present disclosure areillustrative rather than comprehensive. It will be apparent to thoseskilled in the art that many modifications, both to materials andmethods, may be practiced without departing from the scope of thedisclosure.

Ibrutinib prodrugs of Formula (I) can be prepared according to SchemesI-A and I-B:

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically effective amount of a compound of Formula (I)together with a suitable amount of one or more pharmaceuticallyacceptable vehicles so as to provide a composition for properadministration to a patient. Suitable pharmaceutical vehicles aredescribed in the art.

In certain embodiments, a compound of Formula (I) may be incorporatedinto pharmaceutical compositions to be administered orally. Oraladministration of such pharmaceutical compositions may result in uptakeof a compound of Formula (I) throughout the intestine and entry into thesystemic circulation. Such oral compositions may be prepared in a mannerknown in the pharmaceutical art and comprise a compound of Formula (I)and at least one pharmaceutically acceptable vehicle. Oralpharmaceutical compositions may include a therapeutically effectiveamount of a compound of Formula (I) and a suitable amount of apharmaceutically acceptable vehicle, so as to provide an appropriateform for administration to a patient.

Compounds of Formula (I) may be incorporated into pharmaceuticalcompositions to be administered by any other appropriate route ofadministration including intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intracerebral, intravaginal, transdermal, rectal, inhalation, ortopical.

Pharmaceutical compositions comprising a compound of Formula (I) and maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping, or lyophilizing processes. Pharmaceutical compositions maybe formulated in a conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients, or auxiliaries, whichfacilitate processing of compounds of Formula (I) or crystalline formsthereof and one or more pharmaceutically acceptable vehicles intoformulations that can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions provided by the present disclosure may take the form ofsolutions, suspensions, emulsion, tablets, pills, pellets, capsules,capsules containing liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for administration to a patient.

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. A unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof a compound of Formula (I) calculated to produce an intendedtherapeutic effect. A unit dosage form may be for a single daily dose,for administration 2 times per day, or one of multiple daily doses,e.g., 3 or more times per day. When multiple daily doses are used, aunit dosage form may be the same or different for each dose. One or moredosage forms may comprise a dose, which may be administered to a patientat a single point in time or during a time interval.

Pharmaceutical compositions comprising a compound of Formula (I) may beformulated for immediate release.

In certain embodiments, an oral dosage form provided by the presentdisclosure may be a controlled release dosage form. Controlled deliverytechnologies can improve the absorption of a drug in a particular regionor regions of the gastrointestinal tract. Controlled drug deliverysystems may be designed to deliver a drug in such a way that the druglevel is maintained within a therapeutically effective window andeffective and safe blood levels are maintained for a period as long asthe system continues to deliver the drug with a particular releaseprofile in the gastrointestinal tract. Controlled drug delivery mayproduce substantially constant blood levels of a drug over a period oftime as compared to fluctuations observed with immediate release dosageforms. For some drugs, maintaining a constant blood and tissueconcentration throughout the course of therapy is the most desirablemode of treatment. Immediate release of drugs may cause blood levels topeak above the level required to elicit a desired response, which maywaste the drug and may cause or exacerbate toxic side effects.Controlled drug delivery can result in optimum therapy, and not only canreduce the frequency of dosing, but may also reduce the severity of sideeffects. Examples of controlled release dosage forms include dissolutioncontrolled systems, diffusion controlled systems, ion exchange resins,osmotically controlled systems, erodable matrix systems, pH independentformulations, gastric retention systems, and the like.

An appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of a compound ofFormula (I) the stability of a compound of Formula (I) in thegastrointestinal tract, the pharmacokinetics of a compound of Formula(I) and the intended therapeutic profile. An appropriate controlledrelease oral dosage form may be selected for a particular compound ofFormula (I). For example, gastric retention oral dosage forms may beappropriate for compounds absorbed primarily from the uppergastrointestinal tract, and sustained release oral dosage forms may beappropriate for compounds absorbed primarily from the lowergastrointestinal tract. Certain compounds are absorbed primarily fromthe small intestine. In general, compounds traverse the length of thesmall intestine in about 3 to 5 hours. For compounds that are not easilyabsorbed by the small intestine or that do not dissolve readily, thewindow for active agent absorption in the small intestine may be tooshort to provide a desired therapeutic effect.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may be practiced with dosage forms adapted to providesustained release of a compound of Formula (I) upon oral administration.Sustained release oral dosage forms may be used to release drugs over aprolonged time period and are useful when it is desired that a drug ordrug form be delivered to the lower gastrointestinal tract. Sustainedrelease oral dosage forms include any oral dosage form that maintainstherapeutic concentrations of a drug in a biological fluid such as theplasma, blood, cerebrospinal fluid, or in a tissue or organ for aprolonged time period. Sustained release oral dosage forms includediffusion-controlled systems such as reservoir devices and matrixdevices, dissolution-controlled systems, osmotic systems, anderosion-controlled systems. Sustained release oral dosage forms andmethods of preparing the same are well known in the art.

An appropriate dose of a compound of Formula (I) or pharmaceuticalcomposition comprising a compound of Formula (I) may be determinedaccording to any one of several well-established protocols. For example,animal studies such as studies using mice, rats, dogs, and/or monkeysmay be used to determine an appropriate dose of a pharmaceuticalcompound. Results from animal studies may be extrapolated to determinedoses for use in other species, such as for example, humans.

Uses

The methods described herein include administering to a subject in needa composition containing a therapeutically effective amount of one ormore irreversible Btk inhibitor compounds described herein. Withoutbeing bound by theory, the diverse roles played by Btk signaling invarious hematopoietic cell functions, e.g., B-cell receptor activation,suggests that small molecule Btk inhibitors are useful for reducing therisk of or treating a variety of diseases affected by or affecting manycell types of the hematopoetic lineage including, e.g., autoimmunediseases, heteroimmune conditions or diseases, inflammatory diseases,cancer (e.g., B-cell proliferative disorders), and thromboembolicdisorders. Further, the irreversible Btk inhibitor compounds describedherein can be used to inhibit a small subset of other tyrosine kinasesthat share homology with Btk by having a cysteine residue (including aCys 481 residue) that can form a covalent bond with the irreversibleinhibitor. See, e.g., protein kinases in FIG. 1. Thus, a subset oftyrosine kinases other than Btk are also expected to be useful astherapeutic targets in a number of health conditions.

In some embodiments, the methods described herein can be used to treatan autoimmune disease, which includes, but is not limited to, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia.

In some embodiments, the methods described herein can be used to treatheteroimmune conditions or diseases, which include, but are not limitedto graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis.

In further embodiments, the methods described herein can be used totreat an inflammatory disease, which includes, but is not limited toasthma, inflammatory bowel disease, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

In yet other embodiments, the methods described herein can be used totreat a cancer, e.g., B-cell proliferative disorders, which include, butare not limited to diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplamacytic lymphoma/Waldenströmmacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In further embodiments, the methods described herein can be used totreat thromboembolic disorders, which include, but are not limited tomyocardial infarct, angina pectoris (including unstable angina),reocclusions or restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemia, peripheral arterial occlusive disorders,pulmonary embolisms, and deep venous thromboses.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known in the art. See, e.g., Harrison'sPrinciples of Internal Medicine©,” 16th ed., 2004, The McGraw-HillCompanies, Inc. Dey et al. (2006), Cytojournal 3(24), and the “RevisedEuropean American Lymphoma” (REAL) classification system (see, e.g., thewebsite maintained by the National Cancer Institute).

A number of animal models of are useful for establishing a range oftherapeutically effective doses of irreversible Btk inhibitor compoundsfor treating any of the foregoing diseases.

For example, dosing of irreversible Btk inhibitor compounds for treatingan autoimmune disease can be assessed in a mouse model of rheumatoidarthritis. In this model, arthritis is induced in Balb/c mice byadministering anti-collagen antibodies and lipopolysaccharide. SeeNandakumar et al. (2003), Am. J. Pathol 163:1827-1837.

In another example, dosing of irreversible Btk inhibitors for thetreatment of B-cell proliferative disorders can be examined in, e.g., ahuman-to-mouse xenograft model in which human B-cell lymphoma cells(e.g. Ramos cells) are implanted into immunodeficient mice (e.g., “nude”mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

The therapeutic efficacy of the compound for one of the foregoingdiseases can be optimized during a course of treatment. For example, asubject being treated can undergo a diagnostic evaluation to correlatethe relief of disease symptoms or pathologies to inhibition of in vivoBtk activity achieved by administering a given dose of an irreversibleBtk inhibitor. Cellular assays known in the art can be used to determinein vivo activity of Btk in the presence or absence of an irreversibleBtk inhibitor. For example, since activated Btk is phosphorylated attyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specificimmunocytochemical staining of P-Y223 or P-Y551-positive cells can beused to detect or quantify activation of Bkt in a population of cells(e.g., by FACS analysis of stained vs unstained cells). See, e.g.,Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus,the amount of the Btk inhibitor inhibitor compound that is administeredto a subject can be increased or decreased as needed so as to maintain alevel of Btk inhibition optimal for treating the subject's diseasestate.

Administration

Compounds of Formula (I) and pharmaceutical compositions thereof may beadministered orally or by any other appropriate route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa,etc.). Other suitable routes of administration include, but are notlimited to, intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intracerebral,intravaginal, transdermal, rectal, inhalation, or topical.

Administration may be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc.) that may be used to administer a compound and/orpharmaceutical composition.

The amount of a compound of Formula (I) that will be effective in thetreatment of a disease in a patient will depend, in part, on the natureof the condition and can be determined by standard clinical techniquesknown in the art. In addition, in vitro or in vivo assays may beemployed to help identify optimal dosage ranges. A therapeuticallyeffective amount of a compound of Formula (I) to be administered mayalso depend on, among other factors, the subject being treated, theweight of the subject, the severity of the disease, the manner ofadministration, and the judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose may beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information may be used to more accurately determineuseful doses in humans. One having ordinary skill in the art mayoptimize administration to humans based on animal data.

A dose may be administered in a single dosage form or in multiple dosageforms. When multiple dosage forms are used the amount of compoundcontained within each dosage form may be the same or different. Theamount of a compound of Formula (I) contained in a dose may depend onthe route of administration and whether the disease in a patient iseffectively treated by acute, chronic, or a combination of acute andchronic administration.

In certain embodiments an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) or the LD₁₀₀ (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, a compound of Formula (I) may exhibit ahigh therapeutic index. The data obtained from these cell culture assaysand animal studies may be used in formulating a dosage range that is nottoxic for use in humans. A dose of a compound of Formula (I) provided bythe present disclosure may be within a range of circulatingconcentrations in for example the blood, plasma, or central nervoussystem, that include the effective dose and that exhibits little or notoxicity. A dose may vary within this range depending upon the dosageform employed and the route of administration utilized. In certainembodiments, an escalating dose may be administered.

Combination Therapy

The irreversible Btk inhibitor compositions described herein can also beused in combination with other well known therapeutic reagents that areselected for their therapeutic value for the condition to be treated. Ingeneral, the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of the skilledclinician. The initial administration can be made according toestablished protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician.

In certain instances, it may be appropriate to administer at least oneirreversible Btk inhibitor compound described herein in combination withanother therapeutic agent. By way of example only, if one of the sideeffects experienced by a patient upon receiving one of the irreversibleBtk inhibitor compounds described herein is nausea, then it may beappropriate to administer an anti-nausea agent in combination with theinitial therapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literatureCombination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I) described herein) may be administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsmay be provided in a single, unified form, or in multiple forms (by wayof example only, either as a single pill or as two separate pills). Oneof the therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, the dosageregimen actually employed can vary widely and therefore can deviate fromthe dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms, withinthe first 6 hours of the onset of the symptoms, or within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. A compound should be administered as soon as is practicableafter the onset of a disease or condition is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. The length oftreatment can vary for each subject, and the length can be determinedusing the known criteria. For example, the compound or a formulationcontaining the compound can be administered for at least 2 weeks,between about 1 month to about 5 years, or from about 1 month to about 3years.

Exemplary Therapeutic Agents for Use in Combination with an IrreversibleBtk Inhibitor Compound

Where the subject is suffering from or at risk of suffering from anautoimmune disease, an inflammatory disease, or an allergy disease, anirreversible Btk inhibitor compound can be used in with one or more ofthe following therapeutic agents in any combination: immunosuppressants(e.g., tacrolimus, cyclosporin, rapamicin, methotrexate,cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, orFTY720), glucocorticoids (e.g., prednisone, cortisone acetate,prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,or anticholinergics.

Where the subject is suffering from or at risk of suffering from aB-cell proliferative disorder (e.g., plasma cell myeloma), the subjectedcan be treated with an irreversible Btk inhibitor compound in anycombination with one or more other anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossyphol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as Taxotere™. Compounds that havethe basic taxane skeleton as a common structure feature, have also beenshown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with anirreversible Btk inhibitor compound include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies(e.g., rituxan).

Other anti-cancer agents that can be employed in combination with anirreversible Btk inhibitor compound include Adriamycin, Dactinomycin,Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin II (including recombinant interleukin II, or rIL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer agents that can be employed in combination with anirreversible Btk inhibitor compound include: 20-epi-1, 25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; R11 retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived 1; sense oligonucleotides; signaltransduction inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide;tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;telomerase inhibitors; temoporfin; temozolomide; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; totipotent stem cell factor; translation inhibitors;tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBCinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with anirreversible Btk inhibitor compound include alkylating agents,antimetabolites, natural products, or hormones, e.g., nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with an irreversibleBtk inhibitor compound include but are not limited to vinca alkaloids(e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents that can be employed in combination anirreversible Btk inhibitor compound include, but are not limited to,nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with anirreversible Btk inhibitor compound include, but are not limited to,adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions described herein forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with an irreversible Btk inhibitor compound include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Where the subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject can be treated withan irreversible Btk inhibitor compound in any combination with one ormore other anti-thromboembolic agents. Examples of anti-thromboembolicagents include, but are not limited any of the following: thrombolyticagents (e.g., alteplase anistreplase, streptokinase, urokinase, ortissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran(e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux,draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, orBIBR 1048.

EXAMPLES

The following examples describe in detail the synthesis of ibrutinibprodrugs of Formula (I), properties of ibrutinib prodrugs of Formula(I), and uses of ibrutinib prodrugs of Formula (I). It will be apparentto those skilled in the art that many modifications, both to materialsand methods, may be practiced without departing from the scope of thedisclosure.

All reagents and solvents that can be purchased from commercialsuppliers may be used without further purification or manipulation.Non-commercially available reagents may be synthesized from commerciallyavailable starting materials, and by adapting methods well known in theart.

Analytical LC/MS was performed on an Agilent 1100 equipped with AB SciexAPI 2000 or a Waters 2790 equipped with a Waters Micromass QZ massspectrometer and a Phenomenex Luna C-18 analytical column. PreparativeHPLC purification was performed on an Agilent 1100. Both analytical andpreparative HPLC used acetonitrile/water gradients containing 0.05%formic acid. Normal-phase silica gel purification was performed on aISCO CombiFlash Companion purification system using either a mixture ofmethanol and dichloromethane or ethyl acetate and hexanes. Chemicalnames were generated with Accelrys Draw 4.1 SP1, version MDL.Draw.Editor4.1. 100.70 (Accelrys, Inc., San Diego, Calif.).

Example 1[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-yl]carbamoyloxymethylacetate (1)

A mixture of ibrutinib (15 mg, 1.0 eq),(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq), andNaHCO₃ (3.0 eq) in 1:1 water and acetonitrile (0.5 mL) was stirred at20° C. overnight. The reaction was then purified by reverse-phase (C-18)liquid chromatography using water and acetonitrile as eluents to yieldcompound (1). MS (ESI): m/z 557.2 (M+H)+.

Alternatively, a mixture of ibrutinib (25 mg, 1.0 eq),(2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq), andtriethylamine (3.0 eq) in N,N-dimethylacetamide (DMA) (1.0 mL) wasstirred at 20° C. overnight. The reaction was then purified byreverse-phase (C-18) liquid chromatography using water and acetonitrileas eluents to yield compound (1).

Example 2[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-yl]carbamoyloxymethyl2-methylpropanoate (2)

Compound (2) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl 2-methylpropanoate.MS (ESI): m/z 585.2 (M+H)+.

Example 3[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-yl]carbamoyloxymethylcyclohexanecarboxylate (3)

Compound (3) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethylcyclohexanecarboxylate. MS (ESI): m/z 625.3 (M+H)+.

Example 4[3-(4-Phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-yl]carbamoyloxymethylbenzoate (4)

Compound (4) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl benzoate. MS (ESI):m/z 619.2 (M+H)+.

Example 5 (5-Methyl-2-oxo-1,3-dioxol-4-yl)methylN-[3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-yl]carbamate(5)

Compound (5) was prepared according to the method described in Example 1and substituting (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetatewith (5 -methyl-2-oxo-1,3-dioxol-4-yl)methyl carbonochloridate. MS(ESI): m/z 597.2 (M+H)+.

The invention claimed is:
 1. A compound according to Formula (I):

or a pharmaceutically acceptable solvate, hydrate, or salt thereof,wherein: A is N; each R^(1a), R^(1b), R^(1d), and R^(1e) is H; R^(1c) isphenoxy; R² is H; R³ is the following structure:

Z is selected from the following structures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower heteroalkyl, substituted or unsubstituted lower cycloalkyl,substituted or unsubstituted lower heterocycloalkyl, and substituted orunsubstituted lower aryl, wherein each substituent is independentlyselected from —F, —Cl, —CF₃, —CN, —NO₂, —OH, —OCH₃, and —NH₂.
 2. Thecompound according to claim 1, wherein Z is selected from the followingstructures:

wherein each R¹¹, R¹², and R¹³ is independently selected from H, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl,cyclohexyl, phenyl, and benzyl.
 3. The compound according to claim 1,wherein Z is selected from the following structures:


4. The compound according to claim 1, wherein Z is the followingstructure:


5. The compound according to claim 1, wherein Z is the followingstructure:


6. The compound according to claim 1, wherein A is N; each R^(1a),R^(1b), R^(1d), and R^(1e) is H; R^(1e) is phenoxy; R² is H; R³ is(3R)-1-prop-2-enoyl-3-piperidyl; and Z is selected fromacetoxymethoxycarbonyl, benzoyloxymethoxycarbonyl,cyclohexanecarbonyloxymethoxycarbonyl,(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl, and2-methylpropanoyloxymethoxycarbonyl.
 7. The compound according to claim1, wherein A is N; each R^(1a), R^(1b), R^(1d), and R^(1e) is phenoxy;R² is H; R³ is (3R)-1-prop-2-enoyl-3-piperidyl; and Z is2-methylpropanoyloxymethoxycarbonyl.
 8. The compound according to claim1, wherein the compound is selected from the compounds of Formula(I-A-1), Formula (I-A-3), Formula (I-A-5), Formula (I-A-7), and Formula(I-B-1):


9. The compound according to claim 1, wherein the compound is thecompound of Formula (I-A-1):


10. The compound according to claim 1, wherein the compound is thecompound of Formula (I-A-3):


11. A pharmaceutical composition comprising a pharmaceuticallyacceptable vehicle and a therapeutically effective amount of a compoundselected from the compounds listed in claim
 8. 12. The pharmaceuticalcomposition according to claim 11 wherein the composition is suitablefor oral administration.
 13. The pharmaceutical composition according toclaim 11, wherein the composition is suitable for controlled releaseformulation.
 14. The pharmaceutical composition according to claim 11,wherein the composition is suitable for sustained release formulation.